Histone deacetylase class-I inhibition promotes epithelial gene expression in pancreatic cancer cells in a BRD4- and MYC-dependent manner. Issue 11 (27th March 2017)

• Record Type: Journal Article
• Authors: Mishra, Vivek Kumar; Wegwitz, Florian; Kosinsky, Robyn Laura; Sen, Madhobi; Baumgartner, Roland; Wulff, Tanja; Siveke, Jens T.; Schildhaus, Hans-Ulrich; Najafova, Zeynab; Kari, Vijayalakshmi; Kohlhof, Hella; Hessmann, Elisabeth; Johnsen, Steven A.
• Is Part Of: Nucleic acids research. Volume 45:Issue 11(2017)
• Page Start: 6334
• Page End: 6349
• Publication Date: 2017-03-27
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkx212
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a particularly dismal prognosis. Histone deacetylases (HDAC) are epigenetic modulators whose activity is frequently deregulated in various cancers including PDAC. In particular, class-I HDACs (HDAC 1, 2, 3 and 8) have been shown to play an important role in PDAC. In this study, we investigated the effects of the class I-specific HDAC inhibitor (HDACi) 4SC-202 in multiple PDAC cell lines in promoting tumor cell differentiation. We show that 4SC-202 negatively affects TGFβ signaling and inhibits TGFβ-induced epithelial-to-mesenchymal transition (EMT). Moreover, 4SC-202 markedly induced p21 ( CDKN1A ) expression and significantly attenuated cell proliferation. Mechanistically, genome-wide studies revealed that 4SC-202-induced genes were enriched for Bromodomain-containing Protein-4 (BRD4) and MYC occupancy. BRD4, a well-characterized acetyllysine reader, has been shown to play a major role in regulating transcription of selected subsets of genes. Importantly, BRD4 and MYC are essential for the expression of a subgroup of genes induced by class-I HDACi. Taken together, our study uncovers a previously unknown role of BRD4 and MYC in eliciting the HDACi-mediated induction of a subset of genes and provides molecular insight into the mechanisms of HDACi action in PDAC.